Patent GB-1116432-A (GB)
Title: Biphenylyl aliphatic acids and their salts and esters
IPC: C07C57/58
Filed: 1965-09-07
Abstract: Compounds, mostly novel, of the general formulae <FORM:1116432/C2/1> <FORM:1116432/C2/2> <FORM:1116432/C2/3> <FORM:1116432/C2/4> (wherein R1 is H and R2 is a C1- 5 alkyl or haloalkyl or C2- 5 alkenyl or alkynyl radical, or R1 and R2 together form a methylene, C2- 5 alkylidene or ethylene group, R11 is H and R1 is a halogen atom or a C1- 5 alkoxy group or R1 and R11 are both C1- 5 alkyl groups, R3 and R4 each represent a halogen atom or a C1- 5 alkyl, alkylthio or alkylsulphonyl, di-(C1- 5 alkyl)-sulphamoyl, trihalomethyl, benzylthio, SH, NH2, di-(C1- 5 alkyl)-amino, CN, NO2, CONH2, di-(C1- 5 - alkyl) - carbamoyl, C1- 6 alkanoylamino or phenyl radical, each of n and m is 0, 1 or 2 provided n + m is 1, 2 or 3, or may be zero in Formula IV, and Ra represents H or a C1- 5 alkyl, C3- 5 alkynyl, C3- 6 cycloalkyl, mono- or poly - (C1- 5 alkoxy) - C3- 6 cycloalkyl, aralkyl, phenyl, (C1- 6 alkanoyl)-aminophenyl, carboxyphenyl, carbamoyphenyl, mono- or poly-(C1- 5 alkoxy)-C1- 5 alkyl, C1- 5 polyhydroxyalkyl, di - (C1- 5 alkyl) - amino - C1- 5 alkyl o amino-(C3- 6 cycloalkyl)-methyl radical, with the proviso that if the C atom alpha to the carboxyl group carries two H atoms (I), an alkyl or alkenyl group (II) or two alkyl groups (III) and if also m = 0 and/or R3 is halogen, alkyl or dialkylamino, then n is not 0 and R4 is not alkyl or phenyl) are prepared by the following processes: (I) for free acids I: (A) heating a compound of the general formula <FORM:1116432/C2/5> (wherein R5 and R6 each represent a halogen atom or a C1- 5 alkyl, alkylthio or alkylsulphonyl, di - (C1- 5 alkyl) - sulphamoyl, trihalomethyl, benzylthio, SH, di-(C1- 5 alkyl)-amino, CONH2, di-(C1- 5 alkyl)- carbamoyl, C1- 6 alkanoylamino or phenyl radical) with ammonium polysulphide in a reaction-inert organic solvent or with sulphur in an organic amine, hydrolysing the product with an alkali or alkaline-earth metal base and acidifying, and, if desired, when n + m = 1 or 2, nitrating the product and, if desired, reducing the NO2 group(s) to NH2, and, if desired, replacing NH2 by CN by the Sandmeyer reaction; (B) reacting a compound of the general formula <FORM:1116432/C2/6> (wherein R7 and R8 each represent a halogen atom or a di-(C1- 5 alkyl)-sulphamoyl, NO2, di-(C1- 5 alkyl)-carbamoyl, trihalomethyl, phenyl or C1- 5 alkyl radical) with an alkali or alkaline -earth metal hypohalite in a reaction-inert solvent, consuming the excess of hypohalite with a reducing agent and acidifying the reaction mixture with a mineral acid to form a 4-phenylbenzoic acid of the general formula <FORM:1116432/C2/7> reacting this with an inorganic acid halide in a reaction-inert solvent, reacting the resulting acid halide with diazomethane in a reactioninert solvent at room temperature to form a 4-phenyldiazoacetophenone, and treating this, in the presence of a silver oxide, copper or platinum catalyst, with water to form the desired acid or with a C1- 5 alkanol to form the correspondin ester, which may then be saponified, and then in either case, if desired, reducing NO2 to NH2 and, if desired, dialkylating or acylating the latter or replacing it by SH or CN by diazotization and reaction of the diazonium salt with a C1- 5 alkyl xanthate or cuprous cyanide, and further, if desired, alkylating the SH group or subjecting it to the process-SH--> -SO3H ---> -SO2Cl ---> -SO2N(C1- 5 alkyl)2, or converting -CN to -CONH2 by alkaline hydrolysis; (C) carrying out process (A) with a starting material in which n + m = 0 and mono-, di- or tri-nitrating the resulting 4-biphenylylacetic acid, followed, if desired, by conversion of the NO2 group(s) as in (A); (II) for free acids II: (A) carrying out the following process <FORM:1116432/C2/8> (wherein R0 represents a C1- 5 alkyl radical, R00 represents CH2 or a C2- 5 alkylidene radical, and each of R9 and R10 represents a halogen atom or a C1- 5 alkyl, alkylthio or alkylsulphonyl, di-(C1- 5 alkyl)-sulphamoyl, trihalomethyl, benzylthio, SH, NH2, di-(C1- 5 alkyl)-amino, CN, di-(C1- 5 alkyl)-carbamoyl or phenyl radical, any groups containing active H being benzylated at step 7 and subsequently liberated), followed by hydrolysis of the product of step 8, and, if desired, introducing and converting nitro groups as in (I); (B) carrying out the following process <FORM:1116432/C2/9> (wherein R11 and R12 each represent a halogen atom or a C1- 5 alkyl, alkylthio or alkylsulphonyl, di-(C1- 5 alkyl)-sulphamoyl, NO2, trihalomethyl phenyl-substituted C1- 5 alkyl or di-(C1- 5 alkyl)-carbamoyl radical, R13 represents an alkyl radical, and R* represents an aralkyl or C1- 5 alkyl radical), step 1 being effected with an R13 oxalate in the presence of a strong base derived from an alkali metal, step 2 with an R2 halide and step 3 with an alkali metal alkoxide followed by acidification, the process being followed, if desired, by conversion of NO2 as in (I); (III) for free acids III: (A) (when R11 is H and R1 is halogen or C1- 5 alkoxy) treating a compound of the general formula <FORM:1116432/C2/10> (wherein R14 and R15 each represent a halogen atom or a C1- 5 alkyl, CN, NO2, trihalomethyl, di-(C1- 5 alkyl)-sulphamoyl or di-(C1- 5 alkyl)-carbamoyl radical) with SO2Cl2 and, if desired, reacting the resulting a -chloro compound with Na and a C1- 5 alkanol to replace Cl by C1- 5 alkoxy, or with an alkali metal fluoride to replace Cl by F, or hydrolysing it to replace Cl by OH, converting this to its tosyl ester and reacting the latter with an alkali metal fluoride to form an a -fluoro compound, any of these processes being followed, if desired, by conversion of NO2 as in (I), or also oxidizing -S-(C1- 5 alkyl) to -SO2-(C1- 5 alkyl (when R1 and R11 each represent a C1- 5 alkyl radical) reacting an amide of the general formula <FORM:1116432/C2/11> (wherein R16 and R17 each represent a halogen atom or a C1- 5 alkyl, phenyl, trihalomethyl, di-(C1- 5 alkyl)-sulphamoyl, NO2, CONH2 or di-(C1- 5 alkyl)-carbamoyl radical) with a dehydrating agent to produce the corresponding nitrile, reacting this with a C1- 5 alkyl halide in an inert solvent in the presence of an alkali metal amide or hydride and hydrolysing the resulting a ,a -di-C1- 5 alkyl) -4-biphenylylacetonitrile compound, followed, if desired, by conversion of NO2 as in (I); (IV) for free acids IV: carrying out the following process:  <FORM:1116432/C2/12> (wherein R3 and R4 each represent a halogen atom or a trihalomethyl, C1- 5 alkyl or alkylthio, benzylthio, phenyl or di-(C1- 5 alkyl)-sulphamoyl radical and #j represents phenyl), step 1 being effected by reaction with a (C1- 5 alkoxy) carbonylmethylene triphenylphosphorane in an inert solvent, step 3 by a Grignard reaction and step 5 by oxidation, and the process being followed, if desired, by introduction and conversion of NO2 as in (I) and (III); (V) for the esters, omitting the hydrolysis steps in certain of the foregoing processes, or esterifying the free acids.  Some of the products may be resolved into optically active enantiomorphs. The free acids may also be converted into their salts.  The preparation of the following starting materials and intermediates is described: 31-chloro - 41 - phenylacetophenone, 41 - (p - biphenylyl) -acetophenone, 21 - and 31 - methyl-41 - phenylacetophenone, 21 - chloro - 4 - biphenylyl methyl ketone, 4-(p-nitrophenyl)-benzoic acid, 41-(p-nitrophenyl)-diazoacetophenone, ethyl 41-benzyloxycarbonyl-4-biphenylyl-acetate, ethyl 41 - carboxy - 4 - biphenylylacetate, and 41-fluoro-4-biphenylylacetamide. Pharmaceutical compositions.-Tablets and capsules, having anti-inflammatory activity, contain acids or esters of general Formulae I, II, III, and IV, or non-toxic pharmaceutically acceptable salts of the acids, as active ingredients.